Project Summary Uveal melanoma (UM) is a highly aggressive eye cancer that leads to metastatic death in up to half of patients. UM can be divided into two prognostic groups based on a clinically validated gene expression profile (GEP), with class 1 GEP being associated with good prognosis and class 2 GEP with bad prognosis. Each tumor class is associated with specific driver mutations, several of which were discovered in our laboratory. In particular, the highly metastatic Class 2 tumors are associated with inactivating mutations in the tumor suppressor BAP1. However, a major gap exists in our knowledge of how BAP1 mutations lead to metastatic death, which has thwarted the development of targeted precision therapy. To address this deficiency, my objective is to identify and characterize proteins that interact with BAP1. In preliminary studies, I performed a biotin-labeling mass spectrometry technique called BioID2 and identified HDAC1 as a novel BAP1-interacting protein. Thus, I propose to investigate the role of HDAC1 in mediating the tumor suppressor function of BAP1. I hypothesize that BAP1 regulates the epigenetic functions of HDAC1 by maintaining it in a de-ubiquitinated state. Accordingly, I predict that mutational inactivation of BAP1 deregulates HDAC1, leading to changes in histone acetylation and gene expression that promote tumor progression. I will test this hypothesis with the following Aims: (1) Determine how BAP1 interacts with HDAC1 and regulates its ubiquitination state, and (2) Identify how BAP1 loss deregulates transcription through histone acetylation changes catalyzed by HDAC1. My overall objective is to characterize the BAP1-HDAC1 interaction and the consequences of its disruption by BAP1 mutations as an avenue to discovering new therapeutic strategies.